Egg, DavidSchwab, CharlotteGabrysch, AnnemarieArkwright, Peter DCheesman, EdmundGiulino-Roth, LisaNeth, OlafSnapper, ScottOkada, SatoshiMoutschen, MichelDelvenne, PhilippePecher, Ann-ChristinWolff, DanielKim, Yae-JeanSeneviratne, SuranjithKim, Kyoung-MeeKang, Ji-ManOjaimi, SamarMcLean, CatrionaWarnatz, KlausSeidl, MaximilianGrimbacher, Bodo2023-01-252023-01-252018-09-10http://hdl.handle.net/10668/12992Background: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in CTLA4 can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown. Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled. Results: Among the 184 CTLA4 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected CTLA4 mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated. Conclusion: Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected CTLA4 mutation carriers.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/CMVCTLA4EBVcancer predispositioncombined immunodeficiencymalignancyprimary immunodeficiencyAdenocarcinomaAdolescentAdultAgedCTLA-4 AntigenCohort StudiesEpstein-Barr Virus InfectionsFemaleHerpesvirus 4, HumanHumansLymphomaMaleMiddle AgedMutationPrevalenceRiskStomach NeoplasmsYoung Adultresearch article30250467open access10.3389/fimmu.2018.020121664-3224PMC6140401https://www.frontiersin.org/articles/10.3389/fimmu.2018.02012/pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140401/pdf